Morphine State-dependent Learning Research Articles

Lidocaine Reversible Inactivation of the Central Nucleus of Amygdala Impairs Acquisition, Consolidation, and Retrieval of Morphine State-Dependent Learning in Rat

Background/Aims: Morphine causes state-dependent learning that its mechanism and brain-related structures are not fully understood. This study aimed to determine whether lidocaine reversible inactivation of the central nucleus of the amygdala (CeA) could affect acquisition, consolidation, and retrieval of morphine state-dependent learning. Methods: One hundred twenty male Wistar rats were allocated into 15 experimental groups. Subcutaneous administration of morphine (5 mg/kg) induced morphine state-dependent learning. Intra-CeA injection of Lidocaine hydrochloride was performed 5 min before each morphine session for transient inactivation of the CeA. The step-through latency and the time spent in the dark compartment were measured using passive avoidance learning task. Results: Our results showed that pretraining, posttraining, and pretest inhibition of the CeA severely impaired acquisition, consolidation, and retrieval of morphine state-dependent learning. Conclusion: These data revealed the involvement of the CeA in different stages of memory and morphine state-dependent learning.

The role of nucleus accumbens shell on acquisition and retrieval stages of morphine state dependent learning.

In the present study, the effect of transient inactivation of the shell subregion of the nucleus accumbens (NAC shell) by lidocaine on the acquisition and retrieval stages of passive avoidance learning (PAL) and memory and morphine state-dependent learning (SDL) in male wistar rats was investigated. Adult male wistar rats weighing (220-250 g) were used. Lidocaine hydrochloride was bilaterally injected into the shell area of the nucleus accumbens 5 min before of subcutaneous morphine administration. pre-training and pre-test infusion of lidocaine into the NAC shell significantly impaired PAL and memory. Furthermore, Pre-training administration of morphine (5 mg/kg, s.c.) in a step-through passive avoidance task induced state-dependent learning with impaired memory retrieval on the test day. The impairment of memory was restored after pre-test administration of the same dose of morphine. This phenomenon has been named as morphine state dependent learning (SDL). Moreover, Pre-training and pre-test inactivation of the NAC shell impaired morphine SDL. The results suggest the role of NAC shell as a common structure in the PAL and morphine SDL. It is suggested that NAC shell as a common area plays a critical role in the acquisition and retrieval stages of PAL and also morphine SDL.

Blockade of dorsal hippocampal orexin-1 receptors impaired morphine-induced state-dependent learning

Behavioral abnormalities associated with opiate addiction include memory and learning deficits, which are the result of some alterations in the neuromodulatory systems. Recently, orexin has shown to influence drug addiction neural circuitry, specifically in mediating reward-related perception and memory. To explore the possible interaction of orexinergic and opioidergic system on modulation of learning and memory, we have investigated the effects of intra-dorsal hippocampal (intra-CA1) administration of orexin-1 receptor agonist and the competitive orexin-1 antagonist, SB-334867, on morphine-induced memory impairment by using step-down passive avoidance task in mice. Pre-training injection of morphine (5mg/kg, i.p.) impaired memory, which was restored when 24h later the same dose of the drug was administered. Pre-test administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) had not a significant effect on the retention latency compared to the saline-treated animals, but it restored the memory impairment induced by pre-training morphine (5mg/kg, i.p.). Pre-test administration of SB-334867 (10, 20 and 40nmol, intra-CA1) by itself decreased the retention latencies of passive avoidance task. Co-administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) and morphine (1mg/kg, i.p.) on the test day induced morphine state-dependent memory. Conversely, pre-test injection of SB-334867 (10, 20 and 40nmol, intra-CA1) inhibited the orexin-1-induced potentiation of morphine state-dependent learning on the test day. It is concluded that dorsal hippocampal orexin-1 receptors may be involved, at least in part, in morphine state-dependent learning in mice.

Role of hippocampal CA1 area gap junction channels on morphine state-dependent learning

Morphine produces a state dependent learning. The hippocampus is involved in this kind of learning. Gap junctions (GJs) are involved in some of the effects of morphine and exist in different areas of the hippocampus. We investigated the effects of blocking GJ channels of the hippocampal CA1 area, by means of pre-test bilateral injection of carbenoxolone (CBX), on morphine state dependent learning, using a passive avoidance task. Post-training subcutaneous administrations of morphine (0.5, 2.5, 5 and 7.5mg/kg) dose-dependently impaired memory retrieval. Pre-test administration of morphine (0.5, 2.5, 5 and 7.5mg/kg) induced a state-dependent retrieval of the memory acquired under post-training morphine influence. Pre-test injections of CBX (25, 75 and 150nM) dose dependently prevented memory retrieval by post-training (7.5mg/kg) and pre-test (0.5, 2.5, 5, 7.5mg/kg) injections of morphine. The results suggest that intercellular coupling via GJ channels of the hippocampal CA1 area modulates morphine state dependent learning.

Evaluating the Effects of Estradiol Valerate and Raloxifene towards Morphine State-Dependent Learning in Mice

Aims: The aim of this study was to evaluate the possible effects of estradiol valerate and a specific estrogen receptor modulator, raloxifene on passive avoidance learning in male mice and to determine whether there is an interaction between estrogen receptor binding drugs and morphine. Study Design:In this study, the state -dependent learning for morphine was evaluated at the first step, and then the effects of raloxifene and estra diol on thischaracteristicof

Intradorsal hippocampal microinjection of lithium reverses morphine-induced impairment of memory in mice: interactions with dopamine receptor mechanism(s)

In this study, the influence of lithium administration on morphine-induced memory impairment and possible interactions with dopamine receptor mechanism have been investigated. Considering that the dorsal hippocampus is involved in memory, lithium and dopamine agents were injected into the CA1 regions of this site (intra-CA1). For memory assessment, a one-trial step-down inhibitory avoidance task was used in adult male mice. The results showed that posttraining subcutaneous administration of morphine (5 mg/kg) decreased the step-down latency on the test day, and this effect was reversed by pretest administration of the drug, which may be a form of morphine state-dependent learning. Interestingly, pretest intra-CA1 microinjection of different doses of lithium (2 and 4 microg/mouse) reversed memory impairment induced by posttraining morphine (5 mg/kg, subcutaneously). In contrast, pretest intra-CA1 administration of either D1 receptor antagonist SCH23390 (0.01-1 microg/mouse) or D2 receptor antagonist sulpiride (5-10 microg/mouse) inhibited the improvement of memory retrieval by lithium (4 microg/mouse, intra-CA1). Single pretest administration of SCH23390 or sulpiride neither elicited any response, nor reversed morphine-induced amnesia. In conclusion, it can be suggested that the dorsal hippocampal dopaminergic system is involved in the improving response of lithium on morphine-induced amnesia.

Modulation of morphine state-dependent learning by muscarinic cholinergic receptors of the ventral tegmental area

In the present study, the effects of bilateral intra-ventral tegmental area (intra-VTA) injections of an anticholinesterase, physostigmine and/or muscarinic acetylcholine receptor antagonist, atropine on memory retention and morphine state-dependent learning were examined in adult male Wistar rats. As a model of learning, a step-through passive avoidance task was used. Post-training subcutaneous administration of morphine (0.5, 2.5 and 5 mg/kg) dose-dependently impaired memory retrieval on the test day. Pre-test administration of morphine (2.5 and 5 mg/kg) induced state-dependent retrieval of the memory acquired under post-training morphine influence. Pre-test intra-VTA microinjection of physostigmine (0.5, 1 and 2 μg/rat) or atropine (1, 2 and 3 μg/rat) alone cannot affect memory retention. Interestingly, pre-test intra-VTA administration of physostigmine (1 and 2 μg/rat) reversed post-training morphine (5 mg/kg, s.c.)-induced retrieval impairment. Furthermore, pre-test intra-VTA microinjection of physostigmine (1 and 2 μg/rat) with an ineffective dose of morphine (0.5 mg/kg), synergistically improved memory performance impaired by post-training morphine. On the other hand, pre-test intra-VTA microinjection of atropine (2 and 3 μg/rat) 5 min before the administration of morphine (5 mg/kg, s.c.) dose-dependently inhibited morphine state-dependent memory. Pre-test atropine microinjection also reversed the influence of physostigmine on morphine response. It may be concluded that the muscarinic acetylcholine receptors of the VTA play an important role in morphine-induced recovery of memory, on the test day.

Potentiation of acetylcholine action in the ventral tegmental area facilitates morphine-state dependent learning

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N-Methyl- d-aspartate receptors in the ventral tegmental area are involved in retrieval of inhibitory avoidance memory by nicotine

The interaction of opiate, cholinergic, glutamatergic and (possibly) dopaminergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is certainly a topic of great interest. In the present study, the effect of intra-VTA administration of N-methyl- d-aspartate (NMDA) receptor agents on nicotine’s effect in morphine state-dependent learning was investigated. An inhibitory avoidance (IA) task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5 mg/kg) immediately after training decreased IA response on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state-dependency. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in IA response because of post-training morphine (5 mg/kg). Here, we also show that when infused into the VTA before testing, NMDA (0.01 and 0.1 μg/rat) reverse the post-training morphine effect on memory. In addition, the sub-effective doses of NMDA (0.0001 and 0.001 μg/rat) in combination with a low dose of nicotine (0.1 mg/kg) which had no effects by themselves, synergistically improved retrieval of IA memory on the test day. In contrast, pre-test administration of a competitive NMDA receptor antagonist D-AP5 (0.5, 1 and 2 μg/rat) which had no effect alone prevented the nicotine reversal of morphine effect on memory. Our data indicate that NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency.

Morphine State-Dependent Learning Sensitization and Interaction with Nitric Oxide

In the present study, the effects of nitric oxide (NO) precursor L-arginine and L-NAME, a potent inhibitor of NO synthase (NOS), on the expression of sensitization of morphine were investigated. Pre-training administration of morphine (5 mg/kg) impaired memory retrieval compared to pre-training saline-treated animals. Amnesia due to pre-training morphine (5 mg/kg) was restored by pre-test morphine (5 mg/kg).The retrieval impairment was also inhibited in mice which had received once-daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days, followed by 5 days of no drug treatment before training (in order to induce morphine sensitization). Administration of L-arginine (60 mg/kg/day – 3 days) or L-NAME (20 mg/kg/day – 3 days) before training did not alter morphine state dependency. During acquisition of sensitization, administration of L-arginine (60 mg/kg) 20 min before morphine (10 mg/kg/day, for 3 days) increased, while injection of L-NAME (20 mg/kg) 20 min before morphine (30 mg/kg/day, for 3 days) decreased morphine state dependency. It is concluded that NO is involved in the morphine-induced sensitization.

Influence of acute and sub-chronic nicotine pretreatment on morphine state-dependent learning

In the present study, the effects of acute and sub-chronic pretreatment of nicotine on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pre-training administration of morphine (5 mg/kg) decreased the learning of a one-trial passive avoidance task, which was reversed by pre-test administration of the same dose of morphine. Amnesia induced by pre-training morphine was also significantly reversed in nicotine (0.001, 0.01 and 0.1 mg/kg)-treated animals on the test day. Morphine induced amnesia was also reversed in animals which had previously received sub-chronic injections of nicotine, once daily for 3 days followed by 14 days of no drug treatment. The restoration of memory by pre-test morphine was also reduced in animals which had previously received once daily injections of atropine (0.25, 0.5 and 1 mg/kg, i.p.) for 3 days after 14 of being days drug free. In the animals, restoration of memory by sub-chronic nicotine administration, was also decreased by once daily administration of atropine (0.25, 0.5 and 1 mg/kg) 10 min prior to injection of nicotine (0.1 μg/kg/day, for 3 days) but not with SCH 23390; R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine HCl (0.01, 0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) during 3-days of treatment with nicotine. The results suggest that nicotine may induce sensitization which affects the impairment of memory formation via cholinergic but not dopaminergic systems.

Effect of the GABAergic System on Memory Formation and State-Dependent Learning Induced by Morphine in Rats

In the present study, the effects of intraperitoneal injections of GABA_A receptor agonist and antagonist on memory formation and morphine state-dependent learning were investigated in rats. Pre-training administration of morphine (1–15 mg/kg) in a step-down passive avoidance task induced state-dependent learning with impaired memory retrieval on the test day. The impairment of memory was restored after the pre-test administration of the same dose of morphine. The pre-test administration of the GABA_A receptor agonist, muscimol (0.01, 0.05 and 0.1 mg/kg), significantly decreased state-dependent retrieval induced by pre-test morphine (5 mg/kg). The state-dependency effect of morphine (1 mg/kg) was significantly potentiated by the pre-test administration of the GABA_A receptor antagonist, bicuculline (0.125, 0.25 and 0.5 mg/kg). Furthermore, the pre-training injection of muscimol (0.01 mg/kg) impaired memory retrieval which was restored by pre-test morphine (1, 3 and 5 mg/kg) administration. However, the pre-training administration of bicuculline did not affect retention by itself. In addition, amnesia induced by pre-training morphine (5 mg/kg) was significantly reversed in rats which had received pre-test injections of muscimol (0.01, 0.05 and 0.1 mg/kg). Pre-test injections of bicuculline (0.125, 0.25 and 0.5 mg/kg) significantly decreased morphine-induced amnesia. It is concluded that the GABA_A receptor mechanisms may be involved in the memory formation and it is postulated that these receptors may play an important role in morphine state-dependent learning.

INVOLVEMENT OF NMDA RECEPTORS IN MORPHINE STATE–DEPENDENT LEARNING IN MICE

In the present study, the effects of intracerebroventricular (i.c.v.) injection of NMDA receptor agonist and antagonist on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pretraining administration of morphine (5 mg/kg; s.c.) decreased the learning of one-trial passive avoidance task. Pretest administration of morphine (5 mg/kg) induced state-dependent learning acquired under pretraining morphine influence. Pretest administration of NMDA receptor agonist, L-glutamate (0.00001 and 0.0001 and 0.001 μg/mouse, i.c.v.) following pretraining saline treatment did not affect retention. Amnesia induced by pretraining morphine was significantly reversed by pretest administration of L-glutamate (0.0001 and 0.001 μg/mouse, i.c.v.). Pretest administration of noncompetitive NMDA receptor antagonist, MK-801 (0.5, 1, and 2 μg/mouse, i.c.v.) significantly impaired memory formation. Amnesia induced by pretraining morphine was increased by pretest administration of MK-801 (2 μg/mouse, i.c.v.). Pretest coadministration of L-glutamate (0.0001 and 0.001 μg/mouse, i.c.v.) or MK-801 (0.5, 1, and 2 μg/mouse, i.c.v.) with morphine (5 mg/kg, s.c.) increased and decreased morphine state-dependent learning, respectively. The results suggest that NMDA receptors are involved in morphine state–dependent learning in mice.

Discrepancy between effects of milligram and nanogram doses of a COX-2 inhibitor (celecoxib) on morphine state-dependent memory of passive avoidance in mice

This experiment examined and compared the effects of pre-test administration of a selective COX-2 inhibitor (celecoxib), at the doses in the range of mg/kg and ng/kg on morphine state-dependent learning in step-down passive avoidance task in mice. Pre-training administration of 5 mg/kg of morphine-impaired memory retrieval tested 24 h later, which was restored by pre-test administration of the same dose of the drug. Pre-test administration of celecoxib (12.5, 25 and 50 mg/kg), alone or in combination with morphine (1 mg/kg) prevents morphine-induced memory impairment. Ultra-low doses (ULDs) of celecoxib (2, 10 and 50 ng/kg) produced no change in morphine-induced memory impairment. However, co-administration of nanogram doses of celecoxib with 5 mg/kg of morphine in the test day prevented morphine-induced memory improvement, an action different from mg/kg doses. These findings implicate the involvement of COX-2 in memory retrieval and demonstrate that the effect of celecoxib ULD is different from that of mg/kg doses.

The influence of NMDA receptor agonist and antagonist on morphine state-dependent memory of passive avoidance in mice

The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered. To explore the possible involvement of NMDA modulators on morphine-induced memory impairment, we have investigated the effects of intracerebroventricular (i.c.v.) administration of NMDA and the competitive NMDA antagonist, dl-AP5, on morphine-induced memory impairment or recall, on the test day. Morphine (5 mg/kg, s.c.) was administered 30 min before training to induce impairment of memory and 24 h later, 30 min before test to improve it. Pre-test administration of NMDA (0.00001, 0.0001 and 0.001 μg/mouse, i.c.v.) did not alter the retention latency compared to the saline-treated animals. But restored the memory impairment induced by pre-training morphine (5 mg/kg, s.c.). Pre-test administration of dl-AP5 (1, 3.2 and 10 μg/mouse, i.c.v.) by itself decreased the retention latencies. The same doses of dl-AP5 increased pre-training morphine-induced memory impairment. Co-administration of NMDA (0.0001 and 0.001 μg/mouse, i.c.v.) and morphine (5 mg/kg, s.c.) on the test day increased morphine memory improvement. Conversely, dl-AP5 (1, 3.2 and 10 μg/mouse, i.c.v.) inhibited morphine-induced memory recall. It is concluded that NMDA receptors may be involved, at least in part, in morphine state-dependent learning in mice.

Effects of ultra-low doses of morphine, naloxone and ethanol on morphine state-dependent memory of passive avoidance in mice

This experiment examined and compared the effects of pre-test administration of morphine, naloxone and ethanol, at doses in the range of milligram/kg to those of nanogram/kg, on morphine state-dependent learning in a step-down passive avoidance task in mice. Morphine (5 mg/kg) administered before training impaired retention tested 24 hours later, but when the same dose of morphine was also administered before the test, the retention was significantly restored. Pre-training administration of 10 or 20 ng/kg (i.p.) of morphine had no effect, but when co-administered with the same drug at 5 mg/kg (s.c.), it prevented significantly the memory recall improvement after the administration of morphine (5 mg/kg, s.c.) alone. In a parallel experiment, naloxone (5 mg/kg) prevented the memory recall improvement by morphine. However, the effects of naloxone at doses in the range of ng/kg were opposite to those of milligram doses of the same drug. Pre-test administration of ethanol (1 mg/kg) improved memory recall and mimicked the effects of pre-test morphine administration. At doses in the nanogram range, the effects of ethanol were opposite those of mg/kg of the drug. A review of the literature indicates that, for several drugs and chemicals, the effects of nanogram doses are the opposite of the effects of milligrams, because different doses have different sites as well as mechanisms of actions. In conclusion, from the above results one may suggest that, in determination of the dose-response of at least some drugs, the study of the effects of doses much lower than two orders of magnitude of the minimum effective dose are warranted.

Morphine state-dependent learning: sensitization and interactions with dopamine receptors

In the present study, the effects of morphine sensitization on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pretraining administration of morphine (0.5, 2.5 and 5 mg/kg) dose dependently decreased the learning of a one-trial passive avoidance task. Pretest administration of morphine (0.5, 2.5 and 5 mg/kg) induced state-dependent retrieval of the memory acquired under pretraining morphine influence. Pretraining or pretest administration of naloxone (0.25, 0.5 and 1 mg/kg) reversed both responses to morphine (5 mg/kg). Amnesia induced by pretraining morphine was significantly reversed in morphine-sensitized mice which had previously received once daily injections of morphine [20 and 30 mg/kg, subcutaneously (s.c.)] for 3 days. Morphine sensitization tended to reverse but did not significantly affect morphine state-dependent memory. The inhibition of morphine-induced amnesia in morphine-sensitized mice was decreased by once daily administration of naloxone (0.5, 1 and 2 mg/kg) 30 min prior to injection of morphine (20 mg/kg/day×3 days). Three-days administration of 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine HCL (SKF 38393; 8, 16 and 32 mg/kg) or SCH 23390; R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCL (0.01, 0.05 and 0.1 mg/kg) before morphine (for 3 days) and during morphine-sensitization, decreased and increased, the amnesia induced by pretraining morphine, respectively. Similar administration of quinpirole (0.5, 1 and 2 mg/kg) or sulpiride (25, 50 and 100 mg/kg) before morphine also decreased and increased the amnesia induced by pretraining morphine, respectively. The results suggest that morphine sensitization affects the impairment of memory formation, but not the facilitation of retrieval induced by morphine and thus it is postulated that dopamine receptors may play an important role in this effect.

Effect of ethanol on morphine state-dependent learning in the mouse: involvement of GABAergic, opioidergic and cholinergic systems.

We have studied the effect of acute administration of ethanol when it replaced morphine in step-down passive avoidance task on the test day and the effects of antagonists of GABAergic, opioidergic and cholinergic systems on ethanol actions. Morphine (5 mg/kg, s.c.) was administered as pre-training and 24 h later as pre-test drug, and the latencies were measured in mice. Ethanol (0.125, 0.25, 1 and 2 g/kg, i.p.) was administered instead of pre-test morphine. Antagonists of GABAergic (bicuculline 0.5, 1 and 2 mg/kg, i.p.), opioidergic (naloxone 0.06, 0.25 and 1 mg/kg, i.p.) and cholinergic (atropine 0.625 and 1.25 mg/kg, i.p. and mecamylamine 0.5, 1 and 2 mg/kg, i.p.) systems were co-administered with ethanol (0.25 g/kg, i.p.) on the test day. Locomotor activity was measured as well. Pre-training morphine impaired the memory on the test day which was restored when the same dose of morphine was used as pre-test drug. All four doses of ethanol replaced pre-test morphine and enhanced the memory. This effect was prevented by all of the above antagonists. No significant changes were seen in the locomotor activity of the animals treated with ethanol or antagonists compared to the proper controls. GABAergic, endogenous opioidergic and cholinergic systems are involved in the memory recall improvement by ethanol when it replaced morphine on the test day. A review of the literature suggests other possibilities such as the release of intermediate neurotransmitters.